P1‐084: Mitochondrial Genome‐Wide association study of Alzheimer's disease

There is substantial evidence that mitochondrial dysfunction may play a key role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) (Beal 2004). Mitochondrial dysfunction is an early pathomechanism in AD integrating genetic factors related to enhanced amyloid-beta (Aß) production and tau-hyperphosphorylation with aging (Hauptmann et al. 2006; Hirai et al. 2001; Keil et al. 2004; Eckert et al. 2003). Additionally, early defects in glucose utilization in the brains of AD patients suggest possible mitochondrial function abnormalities (Blass et al. 2002; Hoyer et al. 2000), and impairment of mitochondrial oxidative phosphorylation has been extensively reported in AD brains (Chagnon et al. 1995). While the cause of mitochondrial dysfunction in AD is unknown, it has been suggested that genetic defects in the mitochondrial genome may result in mitochondrial dysfunction and increase AD susceptibility. In an attempt to determine whether genetic variation within the mitochondrial genome associates with AD, we have undertaken genome-wide association analyses of the mitochondrial SNPs represented on the Illumina 610-quad chip in a large AD cohort of 4,113 cases and 1,602 controls. This study comprised a sample of 4,113 Alzheimer's disease cases and 1,602 controls. All AD cases met criteria for either probable (NINCDS-AARDA, DSM-IV) or definite (CERAD) AD. Controls were aged 60 years or over and were screened for cognitive decline or neuropathological signs of AD. Genotyping was performed on the Illumina 610-quad chip at the Sanger Institute, UK. After quality control 3,331 cases, 1,221 controls and 138 mitochondrial SNPs remained. SNPs were tested for association with AD using logistic regression, assuming an additive model. Results will be presented at ICAD 2010 A large body of evidence suggests that intervention at the mitochondrial level could ameliorate Aß triggered dysfunction and degeneration, and reduce or alleviate defects in glucose utilization and oxidative phosphorylation in the brains of AD patients. This study investigates mitochondrial genetic variation in a large AD case-control dataset.